OCC Pharmacology of Chemotherapeutic Agents 2 — Questions and Answers
Question 1: Which mechanism explains why irinotecan is considered a prodrug?
- It must be converted by carboxylesterase to the active metabolite SN-38 (Correct answer)
- It requires hepatic CYP3A4 to form its active epoxide form
- Gut bacteria convert it to a glucuronide that re-enters circulation
- It is activated by tumor hypoxia through nitroreduction
Correct answer: It must be converted by carboxylesterase to the active metabolite SN-38
Irinotecan is a prodrug converted by carboxylesterase enzymes to SN-38, its active topoisomerase I inhibitor metabolite.
Question 2: A patient receiving high-dose methotrexate requires leucovorin rescue. What is the primary purpose of leucovorin in this context?
- It competitively bypasses the DHFR block by providing reduced folate (Correct answer)
- It directly inactivates methotrexate in the bloodstream
- It enhances renal elimination of methotrexate
- It replenishes intracellular glutathione stores depleted by methotrexate
Correct answer: It competitively bypasses the DHFR block by providing reduced folate
Leucovorin (folinic acid) is a reduced folate that bypasses the dihydrofolate reductase inhibition caused by methotrexate, rescuing normal cells.
Question 3: Bleomycin exerts its cytotoxic effect primarily through which mechanism?
- Intercalation between DNA base pairs causing strand separation
- Generation of free radicals that cause DNA single- and double-strand breaks (Correct answer)
- Inhibition of topoisomerase II preventing DNA re-ligation
- Covalent crosslinking of DNA strands at guanine N7 positions
Correct answer: Generation of free radicals that cause DNA single- and double-strand breaks
Bleomycin chelates ferrous iron and oxygen to generate reactive oxygen species that cause DNA strand scission, predominantly at G-C sequences.
Question 4: Which pharmacokinetic property of vincristine makes it particularly dangerous if accidentally administered intrathecally?
- High lipophilicity causes rapid CNS accumulation and demyelination
- Extensive protein binding prevents redistribution away from neural tissue
- The drug is irreversibly bound to tubulin in neural cells causing axonal destruction
- Lack of CNS metabolism leads to prolonged exposure causing ascending paralysis and death (Correct answer)
Correct answer: Lack of CNS metabolism leads to prolonged exposure causing ascending paralysis and death
Intrathecal vincristine is uniformly fatal; it causes progressive ascending demyelination and paralysis because there is no mechanism for clearance from CSF.
Question 5: Etoposide's cell-cycle specificity makes it most active against cells in which phase?
- G1 phase, by preventing cyclin D/CDK4 complex formation
- S phase, by incorporating into replicating DNA strands
- Late S and G2 phases, by stabilizing topoisomerase II-DNA cleavable complexes (Correct answer)
- M phase, by binding beta-tubulin and preventing spindle assembly
Correct answer: Late S and G2 phases, by stabilizing topoisomerase II-DNA cleavable complexes
Etoposide stabilizes topoisomerase II cleavable complexes, preventing DNA re-ligation and causing lethal double-strand breaks predominantly in late S and G2 phases.
Question 6: A patient on FOLFOX develops grade 3 peripheral neuropathy. Which agent in this regimen is most responsible?
- 5-Fluorouracil, due to its pyrimidine analog interference with neural RNA
- Leucovorin, due to excessive folate accumulation in nerve cells
- Oxaliplatin, due to platinum-DNA adducts in dorsal root ganglion neurons (Correct answer)
- Both agents contribute equally through synergistic neurotoxicity
Correct answer: Oxaliplatin, due to platinum-DNA adducts in dorsal root ganglion neurons
Oxaliplatin causes cumulative sensory peripheral neuropathy by forming platinum-DNA adducts in dorsal root ganglion neurons, which accumulate with repeated dosing.
Question 7: Why is cyclophosphamide classified as a prodrug requiring hepatic activation?
- The parent compound lacks alkylating activity; CYP2B6 converts it to aldophosphamide which spontaneously forms active phosphoramide mustard (Correct answer)
- It undergoes renal hydroxylation to form its nitrogen mustard active form
- Tumor-specific esterases cleave the phosphate group to release active mechlorethamine
- Gut flora reduce the cyclophosphamide ring to release the active aziridinium ion
Correct answer: The parent compound lacks alkylating activity; CYP2B6 converts it to aldophosphamide which spontaneously forms active phosphoramide mustard
Cyclophosphamide requires hepatic CYP2B6 oxidation to 4-hydroxycyclophosphamide and then aldophosphamide, which spontaneously breaks down to phosphoramide mustard, the active alkylating species.
OCC Pharmacology of Chemotherapeutic Agents 2
Which mechanism explains why irinotecan is considered a prodrug?